1. TDM OF DRUGS USED
IN CARDIOVASCULAR
DISEASES
SENTHIL RAJ V.
PHARM. D. Vth YEAR
2. CARDIOVASCULAR DISEASES
• Cardiovascular drugs are primarily used for the
treatment of angina, arrhythmias & congestive
heart failure.
• Digoxin, used in Congestive heart failure, is
widely prescribed and therapeutically monitored.
• Monitoring & use of anti-arrhythmics such as
disopyramide and lidocaine have been steadily
declining.
• Immunoassay are the used currently the most
popular methods of measuring cardiac drugs.
4. PHARMACOKINETIC PARAMETERS OF
FEW CARDIAC DRUGS
DRUG HALF
LIFE
TIME TO
STEADY
STATE
Vd L/Kg %
PROTEIN
BINDING
THERAPEUTIC
RANGE mg/L
TOXIC
CON.
mg/L
Digitoxin 100-200
days
1 month 0.54 ±
0.14
90 0.01-0.03 >2.5
Digoxin 26-52 5-7 days 7.30 23 0.0005-0.002 >0.003
DisopyramiD
e
5.0-7.0 1-2days 0.59 ±
0.15
28-68 2.0-5.0 >7.0
FlecainiDe 8.0-14 3-5days 4.9 ± 0.4 32-58 0.2-1.0 >1.0
liDocaine 1.4-2.2 0.5-1.5hr
(with
loading
dose);5-
10hr
(without
loading
dose)
1.1 ± 0.4 43-60 1.5-5.0 >6.0
5. CARDIAC GLYCOSIDES
• Digoxin is a cardiac glycoside indicated in the
treatment of atrial fibrillation (AF) and heart failure
(HF).
• Digoxin’s mechanism of action is thought to be
mediated through inotropic effects and
neurohormonal effects.
• Positive inotropic effects from digoxin arise from the
inhibition of Na+–K+-ATPase and secondary
activation of the Na+–Ca2+ membrane exchange
pump resulting in increased force of cardiac
contraction.
6. INDICATIONS FOR TDM DURING
DIGOXIN THERAPY INCLUDES
• Confirmation of toxicity (in the presence of
symptoms of digoxin toxicity)
• Assessing the effect of factors that alter
digoxin’s pharmacokinetics (e.g. renal
impairment, drug interactions)
• Initiating therapy or dose changes (in patients
with renal impairment)
• Therapeutic failure
• Medication adherence
7. SIGNS AND SYMPTOMS OF
TOXICITY
• Common
– Nausea, vomiting, anorexia, fatigue, confusion
• Rare or dose dependant
– Visual disturbances (blurred vision, green-yellow
colour disturbances)
– Cardiac arrhythmias
8. THERAPEUTIC RANGE
Heart failure
– 0.6nmol/L – 1.2nmol/L,
– Toxicity more likely >2.5nmol/L,
– Small increase in mortality with con. >1.5nmol/L.
Atrial Fibrillation (AF)
– 0.6 – 2nmol/L,
– Toxicity more likely >2.5nmol/L
– Serum digoxin levels correlate poorly with ventricular rate.
– In patients who are symptomatic, a low digoxin level may
indicate the patient could benefit from a dose increase.
9. MONITORING REQUIREMENTS
DIGOXIN THERAPY
• Digoxin therapy for HF symptoms has been shown to be
effective at lower concentrations (0.6 to 1.2 nmol/L).
• Therapy in lower concentrations was associated with a small
but significant reduction in all-cause mortality, worsening
heart failure, all-cause hospitalisation and hospitalisation due
to heart failure compared with placebo.
• Higher concentrations (>1.5nmol/L) were associated with a
small but significant increase in all-cause mortality,
cardiovascular mortality and hospitalisation for digoxin-related
toxicity.
to be continued…..
10. • The indications for digoxin TDM are relatively few and
include confirmation of clinically suspected toxicity,
assessing the reasons for therapeutic failure, assessing
medication adherence, and assessing the effects of
factors that alter the pharmacokinetics of digoxin
(predominantly renal dysfunction and drug interactions).
• Samples for digoxin TDM should be taken at least six to
eight hours after the last dose, or ideally immediately
before the next dose.
to be continued…..
11. • This allows for the redistribution of digoxin from plasma
into the tissues.
• It is ideal that digoxin levels are taken when
concentrations are at steady-state.
• The relatively long half-life of digoxin (30 hours in
patients with normal renal function) means that following
initiation or dose alterations, it takes at least 7 days for
steady-state concentrations to be achieved.
• In the elderly with impaired renal function the half life can
be extended to 3.5-5days, meaning 14-20days may be
required before steady state is acheived.
12. ACTIONS ON THERAPEUTIC
LEVEL
• Serum digoxin levels should be interpreted within the
clinical context.
• If the level is above the therapeutic range, the dose
should be reduced even if toxicity is not observed.
• This is based on the observation that the patient is at risk
of arrhythmia, and no further clinical benefit is likely with
higher concentrations.
• Toxicity is observed when digoxin levels are within the
normal range, due to other factors which alter tissue
sensitivity to digoxin.
to be continued…..
14. • Digoxin TDM may be useful to detect the
patients who have a low digoxin concentration
and who may benefit from an increase in digoxin
dose, as opposed to those with higher
concentrations who are likely to develop toxicity
symptoms only from an increase in dose.
15. MEDICATION INTERACTIONS
• Digoxin is rapidly absorbed with a bioavailability of 70-
80% from oral tablets.
• Digoxin is eliminated primarily by renal excretion, via P-
glycoprotein (P-gp).
• Interactions with digoxin are mediated through the
inhibition or induction of P-gp in the GI tract and renally.
• Inhibition of renally located P-gp results in increased
serum digoxin levels.
• Induction of P-gp in the gut reduces digoxin absorption,
resulting in lower levels.
16. MEDICATIONS WHICH INCREASE
THE RISK OF TOXICITY
• Reduce the dose of digoxin prior to initiating therapy:
– Amiodarone (50% dose reduction when initiating amiodarone)
– Verapamil (50% dose reduction when initiating verapamil)
• Monitor digoxin level (7 days-21 days depending on
renal function after introducing the interacting medicine)
– Clarithyromycin / erythromycin / roxithromycin
– Spironolactone
– Cyclosporin
– Itraconazole
– Diltiazem
– Quinine
– Atorvastatin (high doses only 80mg daily)
– Trimethoprim (courses >7 days)
17. • Monitor renal function and potassium level
(every 3-6 months or after vomiting,
diarrhoea or dehydration)
– Diuretics (risk of hypokalaemia)
– ACE-Inhibitors (reduction in renal function –
monitor 7 days after starting then 3-6 monthly)
18. MEDICATIONS WHICH DECREASE
DIGOXIN LEVELS
• Decreased absorption (Monitor Levels 7-21 days after
introducing the interacting medicine)
– Rifampicin
– St John’s Wort
• Decreased absorption (separate administration by 2
hours)
– Antacids (aluminium and magnesium, not calcium based)
19. REFERENCES
• Standards Of Laboratory Practice: Cardiac Drug
Monitoring By Roland Valdes Jr.
• Aged Residential Care Digoxin Monitoring Guidelines
Version 2 2013.
• Appropriateness Of Digoxin Level Monitoring By Mara R.
Mordasinia.
• Cardiovascular Drug Therapy In The Elderly Wilbert S.
Aronow.
